Multiple system atrophy (MSA) is a fatal, progressive neurodegenerative disease that is characterized by
demyelination in the corpus callosum and putamen due to the accumulation of alpha synuclein (a-syn) in glial
cytoplasmic inclusions (GCI) within the oligodendrocytes. Previous data has shown that in post-mortem MSA
brain, a-syn pathology is accompanied by MHCII expression and increased infiltration of peripheral T cells
(CD4+). IFN¿ released from CD4+ T cells enhances inflammation by binding to its receptor (IFN¿R1) and,
through the JAK/STAT pathway, activates MHCII antigen presentation. Other studies have shown, the
neuroinflammation found in post-mortem tissue from MSA patients can be modeled in rodents through a modified
AAV, Olig001-SYN which has a high tropism (>95%) for oligodendrocytes. Moreover, the Oligo001-SYN rodent
model of MSA shows a similar robust CD4+ T cell response due to the oligodendrocyte a-syn expression. My
preliminary results showed there was significant neuroinflammation via increase in IFN¿ and MHCII expression
in the Olig001 mouse model. Additionally, when IFN¿ was knocked down there was a significant reduction in
overall MHCII expression and general neuroinflammation and demyelination. IFN¿ is required for
neuroinflammation and demyelination, however the cell specificity of IFN¿ remains unclear. Therefore, findings
from this proposal can address if Th1 cells (CD4+ T cells that produce IFN¿) are required for MSA pathology.
